Abstract
BackgroundPin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). Juglone (5-hydroxy-1,4-naphthoquinone) is a natural inhibitor of Pin 1 with anti-inflammatory and antifibrotic properties. We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral obstruction (UUO) model and normal rat tubular epithelial cells (NRK52E).ResultsAfter 2 weeks of UUO, immunoblot analyses demonstrated that juglone (0.25 and 1 mg/kg/24 h) inhibited the deposition of matrix (α-smooth muscle actin (SMA), collagen type III and vimentin) and the activation of signaling pathways involved in fibrogenesis (phospho-smad2) and stress response (phospho-heat shock protein (HSP)27). Juglone also reduced EMT (α-SMA and E-cadherin dual staining) and oxidative stress (Mn superoxide dismutase (SOD) and NAPDH oxidase 2 (Nox-2) dual staining) in the obstructed kidney. There was no difference in Pin 1 levels between treatment and control groups. Pin 1 activity was significantly decreased in obstructed kidneys regardless of treatment status. In vitro, juglone (1 μM) significantly decreased α-SMA and p-smad levels compared to vehicle.ConclusionsJuglone attenuates fibrogenesis via Pin 1-independent mechanisms in the UUO model. The antifibrotic effects of juglone may result from the inhibition of smad2 and oxidative stress.
Highlights
Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP)
Immunoblot analyses for Pin 1, biomarkers of matrix remodeling (asmooth muscle actin (SMA), collagen type III and vimentin) and signaling pathways involved in fibrogenesis and stress response (phospho-heat shock protein (HSP)27) demonstrated that juglone therapy decreased a-SMA, collagen type III, vimentin, psmad2 and p-HSP27 levels (Figure 1)
There was no difference in Pin 1 levels between treatment and control groups suggesting that juglone inhibits fibrogenesis independently of Pin 1 levels in the ureteral obstruction (UUO) model
Summary
Pin 1 is a peptidyl-prolyl isomerase inhibitor related to cyclophilin A and FK506 binding protein (FKBP). We evaluated the role of Pin 1 in renal fibrogenesis by evaluating the effects of juglone on epithelial to mesenchymal transition (EMT) and fibrogenesis in the rat unilateral ureteral obstruction (UUO) model and normal rat tubular epithelial cells (NRK52E). Urinary tract obstruction and tubular dilatation result in a series of proinflammatory events that lead to chronic tubulointerstitial fibrosis and kidney failure [1,2]. The rodent unilateral ureteral obstruction (UUO) model has emerged as an important platform for the study of complex cellular interactions that regulate the development of interstitial inflammation, tubular apoptosis and interstitial fibrosis in this milieu [3]. Studies examining the mechanisms of fibrogenesis in UUO may result in the development of therapies that will prevent or reverse the structural and functional consequences of obstructive nephropathy [3]
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